Abstract 1632: An orthotopic model for luciferase-labeled human lung epithelial carcinoma with response to standard of care treatment
Authors: Elizabeth Rainbolt, Andrew Wong, Chassidy Hall, Patrick Wood, Paula L. Miliani De Marval
Journal: Cancer Research (2022)

Abstract The human lung epithelial carcinoma A549 cell line was first developed in 1972 after culturing pulmonary carcinoma tissue from a 58-year-old Caucasian male. Similar to human non-small cell lung carcinoma (NSCLC), this cell line carries a KRAS mutation making an attractive model for drug discovery/oncology research applications. NSCLC tumors grow slower and less aggressively than small cell lung cancers, yet the 5-year survival rate for NSCLC is 25%. Thus, more relevant preclinical models are still needed to evaluate the potential therapeutic activities of agents that can be used in the clinic. Orthotopic implantation of luciferase-labeled cancer cell lines facilitate the evaluation of disease progression using bioluminescence in vivo imaging. Here we report the development of a novel model of orthotopically implanted Luciferase-labeled A549-luc cells, its tumor growth kinetics and response to standard of care therapy. To establish the orthotopic model, we implanted cells by direct injection into the left lung lobe through a small incision on the lateral thorax between the 6th and 7th rib. Disease progression was evaluated by testing cell implants at multiple cell inoculums and following each group for tumor growth using an IVIS Spectrum CT. In line with the observed slow growth of NSCLC, A549 tumor growth kinetics revealed long latency with a median survival of 69.5-days post-implant. Mean flux values correlated with the number of cells inoculated and clinical observations of respiratory distress. Gross necropsies provided visual evidence of masses in the left lung lobe and thoracic cavity. Following the A549-luc orthotopic model development, we sought to evaluate the survival benefit in response to standard of care agents Paclitaxel and the tyrosine kinase inhibitors Erlotinib and Afatinib. Paclitaxel monotherapy was the most active agent in a 101-day study. A single treatment cycle showed robust decrease tumor burden as determined via imaging during the first few weeks following treatment, but disease progression was apparent despite the overall improved survival over the vehicle control group. To establish durable responses, we evaluated the efficacy of Paclitaxel administered for two dosing cycles. Palbociclib, a cyclin-dependent kinase 4/6 inhibitor that has been recently identified as potential target in KRAS-mutant (NSCLC) was also evaluated. Our preliminary results show significant activity for both Palbociclib and Paclitaxel therapies in the A549-luc lung orthotopic xenograft model. This lung orthotopic model provides a sensible alternative that recapitulates the difficulties of treating NCSL tumors in addition to establishing a more clinically relevant model to evaluate cancer therapies compared to standard subcutaneous implanted models. Histopathological analysis of Ki67, Cyclin D1, and CDK4 will be presented from lungs of treated and control groups. Citation Format: Elizabeth Rainbolt, Andrew Wong, Chassidy Hall, Patrick Wood, Paula L. Miliani De Marval. An orthotopic model for luciferase-labeled human lung epithelial carcinoma with response to standard of care treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1632.